Anti-ADAM17 monoclonal antibody MEDI3622 increases IFNγ production by human NK cells in the presence of antibody-bound tumor cells
Several clinically successful tumor-targeting mAbs induce NK cell effector functions. Human NK cells exclusively recognize tumor-bound IgG by the FcR CD16A (FcγRIIIA). Unlike other NK cell activating receptors, the cell surface density of CD16A can be rapidly downregulated in a cis manner by the metalloproteinase ADAM17 following NK cell stimulation in various manners. CD16A downregulation takes place in cancer patients and this may affect the efficacy of tumor-targeting mAbs. We examined the effects of MEDI3622, a human mAb and potent ADAM17 inhibitor, on NK cell activation by antibody-bound tumor cells. MEDI3622 effectively blocked ADAM17 function in NK cells and caused a marked increase in their production of IFNγ. This was observed for NK cells exposed to different tumor cell lines and therapeutic antibodies, and over a range of effector/target ratios. The augmented release of IFNγ by NK cells was reversed by a function-blocking CD16A mAb. In addition, NK92 cells, a human NK cell line that lacks endogenous FcγRs, expressing a recombinant non-cleavable version of CD16A released significantly higher levels of IFNγ than NK92 cells expressing equivalent levels of wildtype CD16A. Taken together, our data show that MEDI3622 enhances the release of IFNγ by NK cells engaging antibody-bound tumor cells by blocking the shedding of CD16A. These findings support ADAM17 as a dynamic inhibitory checkpoint of the potent activating receptor CD16A, which can be targeted by MEDI3622 to potentially increase the efficacy of anti-tumor therapeutic antibodies.
KeywordsImmunotherapy NK cell Cancer Antibody Cytokine Cytotoxicity
Antibody-dependent cell-mediated cytotoxicity
A disintegrin and metalloproteinase-17
We thank Robert Hullsiek, Daniel Mendez, and Dr. Jianming Wu for technical assistance.
Conception and design: HKM and BW. Development of methodology: HKM and BW. Analysis and interpretation of data: HKM, NP, and BW. Writing, review, and/or revision of the manuscript: HKM, NP, and BW. Technical and material support: HKM, NP, EFM. Study supervision: BW.
This study was supported by the Grant R01CA203348 (Walcheck) from the National Institutes of Health.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
Ethical approval and ethical standards
This study was approved by the Institutional Review Board and the Animal Care and Use Committee at the University of Minnesota, 9708M00134 and 1612-34435A, respectively, PI: Bruce Walcheck.
Informed consent was received from each individual who donated peripheral blood for this study.
Adam17flox/flox (Adam17tm1.2Bbl/J) mice and Vav1-Cre mice (B6.Cg-Tg(Vav1-cre)A2Kio/J) were purchased from Jackson Laboratories.
Cell line authentication
The tumor-cell lines in this study are used to determine NK cell reactivity and so the critical feature is their tumor-associated antigen expression (i.e., CD20 and HER2). Cells were routinely checked to ensure consistent levels of antigen expression.
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